HIV-1 is associated with a range of neurocognitive deficits referred to as Human Immunodeficiency Virus-Associated Neurocognitive Disorders (HAND) which can have a dramatic impact on patients' lives. The mechanisms underlying these conditions are not entirely known, but there is evidence of HIV-associated neuropathology in brain areas that are consistent with the behavioral deficits associated with HAND. For instance, there is evidence of pathology in the striatum, which is a component of the mesolimbic dopamine system, and has an important role in functions including but not limited to, motor control, learning and memory, and motivation. One potential mediator of the effects outlined above is the HIV protein Tat. Infected glia release Tat and other viral proteins, as well as proinflammatory cytokines. Tat expression has been associated with synapto-dendritic changes in the striatum, neuroinflammation and alterations in the dopamine system in animal models and HIV patients. Research also suggests increased expression of Tat in patients presenting HIV-associated neuropathology. The underlying mechanisms of Tat-induced neuropathology are an active area of research and convergent data suggest a role for toll-like receptors (TLR) such as TLR4. TLR4 gene expression is correlated with neurodegeneration in HIV patients, and Tat and other HIV proteins increase the expression of TLRs. The deficits produced by HAND are ultimately expressed in the behavior of patients. Therefore, a primary goal of the proposed research is to determine the consequences of Tat expression on intracranial self-stimulation (ICSS) using an inducible Tat transgenic mouse model. ICSS is a preclinical behavioral model that is dependent on brain circuitry that is particularly vulnerable t Tat-induced neuropathology. This model is commonly used to explore the mechanisms underlying the abuse-related effects of drugs, and has also been used to examine mechanisms underlying other human disorders that are associated with dysfunction of forebrain dopaminergic circuitry. This proposal aims to adapt ICSS to examine the behavioral effects of the expression of Tat and to correlate effects on this endpoint with the pathology that has been demonstrated in neuroanatomical models. This proposal will also test the hypothesis that Tat-induced neurotoxicity and behavioral impairment can be blocked by treatment with the TLR4 antagonist (+)naloxone. Together, the aims of this proposal are designed to clarify the functional consequences and mechanisms of Tat-induced neurodegeneration and behavioral impairment, and the TLR4 antagonist (+)naloxone will be evaluated as a candidate medication to treat these HIV-related pathologies.